The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension

Abstract

Context: The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years.

Objective: The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure.

Design, setting, and participants: This was a multicenter, international, open-label study of 4550 women.

Intervention: Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover).

Main outcome measures: Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported.

Results: Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture.

Conclusion: Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.

Trial registration: ClinicalTrials.gov NCT00523341.

Figure 1.

Disposition of all participants. All women who completed FREEDOM (ie, completed their 3 y visit, did not discontinue IP, and did not miss more than one dose) were eligible to participate in the FREEDOM extension. ^a, Two women who discontinued denosumab also entered the extension in the long-term denosumab group.

Figure 2.

Concentrations of the bone turnover markers serum CTX (A) and serum P1NP (B). Data are medians and interquartile ranges. Time points include the following: baseline, month 1, and years 0.5, 1, 2, 3, 3 (day 10), 3.5, 4, 5, and 6. n, number of subjects with observed data.

Figure 3.

Percentage change from FREEDOM baseline in BMD at the lumbar spine (A), total hip (B), femoral neck (C), and 1/3 radius (D). Data are least squares means and 95% confidence intervals. Data are shown for the entire extension study population for the lumbar spine, total hip, and femoral neck sites. Data from the BMD substudy population are shown for the 1/3 radius. This substudy also provided BMD data for early intermediate time points in the parent trial for the lumbar spine (month 1, month 6, year 1, and year 2), total hip (months 1 and 6), and femoral neck (months 1 and 6). ^a, P < .05 compared with FREEDOM baseline; ^b, P < .05 compared with extension baseline. Percentages listed to the right of each graph represent the percentage change in BMD while on denosumab treatment.

Figure 4.

Incidence of new vertebral fractures (A and C) and nonvertebral fractures (B and D). Solid bars represent actual data collected and dashed bars represent virtual placebo data. Percentages for new vertebral fractures are crude incidence and percentages for nonvertebral fractures are Kaplan-Meier estimates. Error bars correspond to 95% confidence intervals.